JP2015143200A - Inhibitors of vcam-1 expression - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide methods for inhibiting VCAM expression, for treating various inflammable diseases, for inhibiting alcoholic hepatic disorders, and for inhibiting reduction in action amount caused by inflammation.SOLUTION: Provided is a composition comprising a turmeric extract, or a turmeric extract and an antioxidant.

Description

  The present invention suppresses a decrease in the amount of behavior caused by inflammation, a composition containing a turmeric extract and an antioxidant, a VCAM-1 expression inhibitory composition, an anti-inflammatory composition, an alcoholic liver disorder inhibitory composition, and It relates to a composition. The present invention also relates to a VCAM-1 expression-suppressing composition containing a turmeric extract, an anti-inflammatory composition, an alcoholic liver disorder-suppressing composition, and a composition that suppresses a decrease in the amount of behavior caused by inflammation.

Vascular cell adhesion molecule-1 (VCAM-1) is a protein having a molecular weight of 110 kDa belonging to the immunoglobulin superfamily, and is expressed in vascular endothelial cells and follicular dendritic cells activated by various chemokines and inflammatory mediators. It is known.
Expression of VCAM-1 is known to cause inflammatory diseases such as arteriosclerosis, rheumatism, asthma, nephritis, encephalomyelitis, hepatitis (patent document 1 and non-patent document 1). Substances that suppress expression are believed to have therapeutic effects in these diseases.

  It is known that chronic alcohol intake increases blood endotoxin concentration, and endotoxin activates liver Kupffer cells to cause liver damage (Non-patent Document 2). On the other hand, it is known that liver damage caused by endotoxin is suppressed by inhibition of VCAM-1 function by administration of anti-VCAM-1 antibody (Non-patent Document 3). Therefore, a substance that suppresses the expression of VCAM-1 is considered to suppress liver damage caused by alcohol intake.

  One of the pathological behaviors in depression, fatigue, alcohol intake, etc. is a decrease in the amount of behavior (Patent Document 2, Non-Patent Document 5 and Non-Patent Document 8). Inflammation is considered to be involved as a cause of these pathological conditions (Non-Patent Documents 4, 9 and 10). It is considered that a substance that suppresses the expression of VCAM-1 can suppress a decrease in the amount of behavior caused by inflammation by suppressing inflammation.

  To date, as a VCAM-1 expression inhibitor, Non-Patent Document 6 discloses that ethyl acetate extract of turmeric and curcumin, which is a component thereof, suppress the expression of VCAM-1 induced by TNF-α. It is shown. Non-Patent Document 7 shows that sesamin analogs suppress the expression of VCAM-1 induced by TNF-α. However, these VCAM-1 expression inhibitor effects are not sufficient, and a method for effectively suppressing the expression of VCAM-1 is required.

JP-A-11-923382 JP 2005-239579 A

J Physiol Pharmacol, 59 Suppl 1: 107-17, 2008 Liver, 42 (1): 1-14, 2001 J Immunol, 158 (12): 5941-8, 1997 Current Drug Abuse Reviews, 3 (2): 110-115, 2010 Alcohol & Alcoholism 43 (2): 124-126, 2008 International Journal of Immunophamacology, 21 (11), 745-757, 1999 Biosci. Biotechnol. Biochem., 74 (8), 1539-1544, 2010 Specialized in Human Sciences Psychology Vol.3, No.1, pp.33-40, 2013 Prog Neuropsychopharmacol Biol Psychiatry. 2005 Feb; 29 (2): 201-17. Sports Med. 2009; 39 (5): 389-422.

  This invention makes it a subject to provide the effective expression suppression method of VCAM-1 in view of the said present condition. The present invention also provides a method for treating various inflammatory diseases caused by the expression of VCAM-1, a method for suppressing liver damage caused by alcohol intake by suppressing the expression of VCAM-1, and a behavioral amount caused by inflammation. Another object is to provide a method for suppressing the decrease.

As a result of intensive studies to solve the above problems, the present inventors have found that the turmeric extract exhibits an excellent VCAM-1 expression inhibitory effect, and further, the combination of the turmeric extract and the antioxidant is The present inventors have found that the extract and the antioxidant are not additive effects combined with the effects of using them alone, but have a surprisingly synergistic VCAM-1 expression suppression effect far exceeding the effects of each of them alone.
In addition to the above, the present inventors have obtained various unexpected new findings as described below, and have further conducted intensive studies to complete the present invention.

That is, the present invention relates to a composition containing the following turmeric extract and antioxidant.
[1] A composition comprising a turmeric extract and an antioxidant.
[2] The composition as described in [1] above, wherein the extraction solvent of the turmeric extract is water and / or a hydrophilic organic solvent.
[3] The composition according to [1] or [2], wherein the turmeric extract contains bisaclone.
[4] The composition according to any one of [1] to [3], wherein the antioxidant is one or more selected from the group consisting of sesamin or an analog thereof, curcumin, and ornithine.
[5] The composition according to any one of [1] to [4], wherein the mixing ratio of bisaclone and the antioxidant is as follows in terms of mass ratio.
Bisaclone: sesamin or its analogs = 1: 3 to 1: 300 or bisaclone: curcumin = 1: 1 to 1: 100 or bisaclone: ornithine = 1: 2 to 1: 200
[6] A VCAM-1 expression-suppressing composition comprising a turmeric extract and an antioxidant.
[7] An anti-inflammatory composition comprising a turmeric extract and an antioxidant.
[8] A composition for suppressing alcoholic liver injury, comprising a turmeric extract and an antioxidant.
[9] A composition that suppresses a decrease in the amount of behavior caused by inflammation, comprising a turmeric extract and an antioxidant.
[10] The composition according to [9], wherein the inflammation is caused by alcohol.
[11] The composition according to any one of [1] to [10] above, which is a preventive, ameliorating, or therapeutic agent for diseases caused by the expression of VCAM-1.
[12] A VCAM-1 expression-suppressing composition, wherein the extraction solvent contains water and / or a turmeric extract that is a hydrophilic organic solvent.
[13] An anti-inflammatory composition comprising a turmeric extract whose extraction solvent is water and / or a hydrophilic organic solvent.
[14] A composition for suppressing alcoholic liver injury, characterized in that the extraction solvent contains water and / or a turmeric extract that is a hydrophilic organic solvent.
[15] A composition for suppressing a decrease in the amount of behavior caused by inflammation, wherein the extraction solvent contains water and / or a turmeric extract that is a hydrophilic organic solvent.
[16] The composition according to [15], wherein the inflammation is caused by alcohol.
While the above [1] to [11] have an antioxidant as an essential constituent along with the turmeric extract, the above [12] to [16] have the turmeric extract as an essential constituent. Oxidizing substances are not an essential component.

  ADVANTAGE OF THE INVENTION According to this invention, the VCAM-1 expression inhibitory effect which increased remarkably compared with the conventional VCAM-1 expression inhibitor can be acquired, and various diseases and various inflammatory diseases mediated by VCAM-1 Can be prevented, ameliorated or treated. Moreover, according to the present invention, liver damage due to alcohol intake can be suppressed, and further, a decrease in the amount of behavior caused by inflammation can be prevented, alleviated or improved.

Comparison of absorbance data reflecting VCAM-1 production on human umbilical vein vascular endothelial cells in combination with control, sesamin 40 μM, and turmeric extract 140 μg / mL (mixture of sesamin 40 μM and turmeric extract 140 μg / mL) is there. Comparison of absorbance data reflecting the amount of VCAM-1 produced on human umbilical vein endothelial cells in combination with control, sesamin 60 μM, and turmeric extract 210 μg / mL (mixture of sesamin 60 μM and turmeric extract 210 μg / mL) is there. Comparison of absorbance data reflecting VCAM-1 production on human umbilical vein endothelial cells in combination with curcumin 3 μM and curcumin extract 48 μg / mL (mixture of curcumin 3 μM and turmeric extract 48 μg / mL) is there. Comparison of absorbance data reflecting VCAM-1 production on human umbilical vein vascular endothelial cells in combination with control, 10 μM curcumin, and 160 μg / mL turmeric extract (mixture of 10 μM curcumin and 160 μg / mL turmeric extract) is there. Comparison of absorbance data reflecting the amount of VCAM-1 produced on human umbilical vein vascular endothelial cells in combination with 40 μM ornithine control and 140 μg / mL turmeric extract (mixture of ornithine 40 μM and turmeric extract 140 μg / mL) is there. It is the data of the AST density | concentration and ALT density | concentration in the mouse | mouth plasma before ethanol administration and 1, 2, 4, 6 hours after administration of a turmeric extract administration group and a control group.

Hereinafter, the present invention will be described in detail.
The composition of the present invention is characterized by containing a turmeric extract or a turmeric extract and an antioxidant.
The composition of the present invention may contain components other than the turmeric extract and the antioxidant.

  In the present invention, “containing” includes a mixed state or a coexisting state. The coexistence state refers to a state in which each is separated before use but is in a combined state in which they are mixed and used at the time of use.

Turmeric extract In the present invention, the term “turmeric extract” refers to an extract (turmeric extract) of a plant raw material derived from a plant belonging to the genus Turmeric belonging to the family Ginger, which is further extracted by heating and / or reduced pressure as necessary. Volatilized and dried. Conventionally known methods can be used for these heating, decompression and drying methods.
Examples of the plant material include Curcuma longa (Curcuma), Curcuma aromatica, Curcuma zedoaria, Curcuma phaeocaulis, Curcuma kwangsiensis, Curcuma wenyujin, and / or Curcuma xanthorrhiza, which are plants belonging to the genus Turmeric. These rhizomes may be collected from the soil, and may be used in the form of an appropriate part of the rhizome as it is or cut into an appropriate size or shape, or in the form of a pulverized product. it can. These plant materials may be appropriately dried.
The extraction method of the turmeric extract from plant raw material is not specifically limited, A conventionally well-known method can be used. Examples of the extraction solvent include water, hot water, a hydrophilic organic solvent, a mixed solvent of water and a hydrophilic organic solvent, and the like. Alcohol, water, a mixed solvent of alcohol and water are preferable, and the alcohol is not particularly limited. Ethanol is preferred. When the composition of the present invention contains a turmeric extract but no antioxidant, the extraction solvent is usually water and / or a hydrophilic organic solvent.
In the present invention, the mixing ratio of the mixed solvent of the hydrophilic organic solvent and water is not particularly limited. For example, the weight ratio is preferably in the range of 10:90 to 90:10, and more preferably in the range of 20:80 to 50:50. preferable. The temperature at the time of extraction is not particularly limited.

  As described in Non-Patent Document 6, the turmeric extract extracted using water and / or a hydrophilic organic solvent as the extraction solvent is extracted using a hydrophobic organic solvent such as ethyl acetate as the extraction solvent. Compared with naturmeric extract, it contains a compound having higher water solubility. Therefore, these extracts are clearly different from each other in the component composition contained.

In the present invention, as the turmeric extract, the turmeric rhizome extract obtained as described above can be used as it is, and the turmeric rhizome extract is further processed by dilution, concentration, drying and the like. It is also possible to use ones that have been subjected to. A conventionally well-known method can be used for methods, such as dilution, concentration, and drying.
The turmeric extract used in the present invention is characterized by containing bisaclone. Bisaclone is preferably contained in an amount of 0.15% by weight or more. The amount of bisaclone in the turmeric extract can be determined by mixing the turmeric extract with ethyl acetate and centrifuging the supernatant from the supernatant to remove ethyl acetate under reduced pressure. It can obtain | require by attaching | subjecting to chromatography (HPLC).

In the present invention, bisaclone is a compound classified as a bisaborane-type sesquiterpene, and means a compound having the following planar structural formula or a salt thereof. Bisaclone has an asymmetric carbon at the position indicated by * in the planar structural formula, and therefore there are several kinds of optical isomers. Bisaclone in this specification is a concept that includes any optical isomers. is there.

Antioxidant Substance The antioxidant substance in the present invention is a general term for substances that attenuate or eliminate harmful reactions involving oxygen in living bodies, foods, daily necessities, and industrial raw materials. In particular, in biochemistry or nutrition, it refers to a substance that suppresses lipid peroxidation in a narrow sense, and in a broad sense, it also includes reactive oxygen species (oxygen free radicals, hydroxyl radicals, It contains substances that contribute to the detoxification reaction by capturing superoxide anions, hydrogen peroxide, etc.). For example, glutathione, N-acetylcysteine, ascorbic acid, α-tocopherol, butylhydroxyanisole, catechin, quercetin, uric acid, bilirubin, flavonoid, ceruloblastine, albumin, ferritin, metallothionein, superoxide dismutase (copper zinc type, manganese type) , Secreted type), glutathione peroxidase (cytoplasmic type, plasma type, phospholipid hydrobeloxide type), glutathione transferase, catalase, thioredoxin (Biochemical Dictionary, Tokyo Chemical Dojin, 1998, 3rd edition), sesamin and its analogs (Vitamin 79 (1), 23-26, 2005), curcumin and its analogs (Biol. Pharm. Bull. 30 (1), 74-78 (2007)).
In addition, the antioxidant substance in the present invention includes a substance that reduces oxidative stress indirectly after being ingested by a living body, such as ornithine. Ornithine, a kind of amino acid, lowers the level of ammonia in the living body (Journal of Hepatology. 26 (1): 174-82, 1997) and oxidative stress induced by ammonia (The Journal of Neuroscinece 26 (18), 4774 -4784 (2006)).

The antioxidant used in the present invention is preferably sesamin or an analog thereof, curcumin, ornithine and the like.
Sesamin or its analogs include sesamin, sesaminol, episesamin, episesaminol, sesamorin, 2- (3,4-methylenedioxyphenyl) -6- (3-methoxy-4-hydroxyphenyl) -3,7 -Dioxabicyclo [3.3.0] octane, 2,6-bis- (3-methoxy-4-hydroxyphenyl) -3,7-dioxabicyclo [3.3.0] octane, or 2- ( 3,4-methylenedioxyphenyl) -6- (3-methoxy-4-hydroxyphenoxy) -3,7-dioxabicyclo [3.3.0] octane and the like, and these are optical isomers. Alternatively, in the case of a stereoisomer, each isomer can be used alone or in a mixed state such as a racemate. Moreover, these can also be used in the form of a glycoside, and these can also be used individually or in combination as appropriate.
Sesamin and its analogs should be separated from sesame oil, sesame seeds and sesame seeds.
In addition to sesame seeds, those separated from natural products containing sesamin such as pentagonal bark, paulownia tree, and white fruit bark may be used. Moreover, you may use what was obtained by the synthesis | combination.
As a method for separating sesamin from sesame oil, sesame seeds and sesame seeds, organic solvents (acetone, methyl ethyl ketone, diethyl ketone, methanol, ethanol, etc.) are used for extraction and concentration, and the solvent is removed by evaporation from the solvent fraction. To obtain (extraction separation method). Further, sesamin and the like may be separated from a distillate containing sesamin obtained by steam distillation of sesame oil under reduced pressure. Since these methods are well established in the past, the present invention may follow them.

As curcumin, a natural product can be used. For example, curcumin extracted from a natural plant containing curcumin may be used. Moreover, you may use what was chemically synthesize | combined by the conventionally well-known method, a commercial item, etc.
As a method of extracting curcumin from natural plants, a conventionally known method can be used. For example, extraction and concentration using an organic solvent (acetone, methyl ethyl ketone, diethyl ketone, methanol, ethanol, etc.) A method obtained by evaporating and removing the solvent from the solvent can be used (extraction separation method). Moreover, the method of extracting by contacting a turmeric with the carbon dioxide gas of a supercritical state can also be used.

Examples of ornithine include L-ornithine, D-ornithine, and salts thereof. Examples of ornithine salts include acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, and the like. Acid addition salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, acetate, maleate, fumarate, citrate, malate, lactate, α-ketoglutarate , Organic acid salts such as gluconate and caprylate.
For ornithine, a chemically synthesized product, a product produced by fermentation, a product obtained by extracting from a raw material such as swordfish, or the like can be used. As these synthesis methods, fermentation production methods and extraction methods, those using conventionally known methods can be used.

In the composition of the present invention containing a turmeric extract and an antioxidant, the blending ratio (mass ratio) of the turmeric extract and the antioxidant is indexed to bisaclone, which is a sesquiterpenoid contained in the turmeric extract. It is preferable that In consideration of bioavailability, the blending ratio (mass ratio) of bisaclone: sesamin or its analog is preferably about 1: 0.3 to 1: 3000, more preferably about 1: 1 to 1: 1000. More preferably about 1: 3 to 1: 300. The mixing ratio (mass ratio) of the turmeric extract and curcumin is preferably such that the mass ratio of bisaclone: curcumin is about 1: 0.1 to 1: 1000, more preferably about 1: 0.3 to 1: 300, more preferably about 1: 1 to 1: 100. The mixing ratio (mass ratio) of the turmeric extract and ornithine is preferably such that the mass ratio of bisaclone: curcumin is about 1: 0.2 to 1: 2000, more preferably about 1: 0.6 to 1: 600, more preferably about 1: 2 to 1: 200.

  The composition of the present invention may further contain one or more components other than essential components (turmeric extract and antioxidant). Ingredients other than essential ingredients are not particularly limited, and are acceptable ingredients in pharmaceuticals, foods and drinks, feeds, food additives, health foods, supplements, feed additives, etc., and can be taken orally There is no particular limitation. As components other than essential components, for example, fructose glucose liquid sugar, dextrin, acidulant, vitamins, thickener, turmeric pigment, inositol, fragrance, cyclic oligosaccharide, sweetener, mineral, antioxidant, emulsifier, etc. Can be mentioned.

Examples of the acidulant include citric acid, malic acid, gluconic acid, tartaric acid, and salts thereof.
Examples of vitamins include niacin, vitamin B1, vitamin B6, vitamin C, vitamin E, and the like.
Thickeners include thickening polysaccharides such as gellan gum, xanthan gum, pectin, guar gum and the like.
The turmeric pigment is obtained by extracting from the rhizome part of turmeric with hot ethanol, hot oil or propylene glycol, or room temperature to hot hexane or acetone, and mainly contains curcumin. . The amount of turmeric pigment in the composition of the present invention is such that curcumin is contained in an amount of about 3 mg to 50 mg, more preferably about 5 mg to 40 mg, particularly preferably about 6 mg to 30 mg per oral intake. It is good to be done.

Examples of the mineral include magnesium, calcium, sodium, potassium and the like.
Examples of the antioxidant include vitamin C and enzyme-treated rutin.
Examples of the sweetener include sugars such as fructose, glucose, and liquid sugar, and high-intensity sweeteners such as honey, sucralose, acesulfame potassium, thaumatin, and aspartame.

The composition of the present invention can be administered orally.
Moreover, the composition of this invention can be used as a pharmaceutical (for humans or animals), food and drink, feed, food additives, health foods, supplements, feed additives and the like.
The shape of the composition of the present invention is not particularly limited, and may be any property such as liquid, fluid, gel, semi-solid, or solid.

  When the composition of the present invention is used as a pharmaceutical, it is preferably administered in the form of a pharmaceutical composition comprising the composition of the present invention and a pharmaceutically acceptable additive for pharmaceutical preparation. The pharmaceutical composition may take the form of oral solid preparations such as capsules, tablets (including coated tablets such as sugar-coated tablets or enteric tablets or multilayer tablets), powders or granules, or oral liquid preparations. Or may be in the form of parenteral preparations such as injections, drops, suppositories and the like. These preparations can be produced by a method known per se.

Additives for pharmaceutical preparations usually used in solid preparations such as capsules, tablets, powders or granules include, for example, excipients (for example, lactose, sucrose, glucose, starch, crystalline cellulose, etc.), binders ( For example, starch paste solution, hydroxypropyl cellulose solution, carmellose solution, gum arabic solution, gelatin solution, sodium alginate solution, etc.), disintegrant (eg starch, carmellose sodium, calcium carbonate etc.), lubricant (eg stearin Magnesium sulfate, talc, stearic acid, calcium stearate, etc.), surfactant (eg, polysorbate 80, polyoxyethylene hydrogenated castor oil, etc.), thickener (eg, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyethylene glycol, etc.) ) Etc. It is, but is not limited thereto. Tablets or granules are
The coating may be applied with a coating agent (for example, gelatin, sucrose, gum arabic, carnauba wax, cellulose acetate phthalate, methacrylic acid copolymer, hydroxypropylcellulose phthalate, carboxymethylethylcellulose, hydroxypropylmethylcellulose, etc.). The capsule may be a microcapsule or a soft capsule in addition to a hard capsule. The solid preparation can be produced by a conventionally known method.

Liquid preparations include, for example, sugars (eg, sucrose, sorbit, fructose, etc.), glycols (eg, polyethylene glycol, propylene glycol, etc.), dispersing or thickening agents (eg, gelatin, gum arabic, hydroxyethyl cellulose, hydroxypropyl). Cellulose, polyvinyl alcohol, polyethylene glycol, etc.), emulsifier (eg, glycerin fatty acid ester, sucrose fatty acid ester, etc.), solubilizer (eg, gum arabic, polysorbate 80, etc.), pH adjuster (eg, citric acid, citric acid, etc.) Trisodium, etc.), preservatives (for example, p-hydroxybenzoates, etc.) and the like may be blended.

  When the composition of the present invention is used as a food or drink, the composition of the present invention may be used as it is, or may be a form containing the composition and an additive acceptable for food hygiene or normal food ingredients. . When using the composition of this invention as a food additive, the form which uses this composition as it is may be sufficient, and the form containing the additive accepted on food hygiene may be sufficient.

  The foods and drinks and food additives include, for example, capsules, tablets (including coated tablets such as sugar-coated tablets or multilayer tablets, or mouth disintegrating agents), powders or granules, together with additives that are acceptable for food hygiene. It may take the form of a solid composition or may take the form of a liquid composition. Examples of the additive include excipients (eg, lactose, dextrin, corn starch, crystalline cellulose, etc.), lubricants (eg, magnesium stearate, sucrose fatty acid ester, glycerin fatty acid ester, etc.), disintegrating agents (eg, Carboxymethyl cellulose calcium, anhydrous calcium hydrogen phosphate, calcium carbonate, etc.), binder (eg starch paste solution, hydroxypropyl cellulose solution, gum arabic solution etc.), solubilizer (eg gum arabic, polysorbate 80 etc.), sweetness (For example, sugar, fructose, glucose liquid sugar, honey, aspartame, etc.), coloring (for example, β-carotene, food tar pigment, riboflavin, etc.), preservative (for example, sorbic acid, methyl paraoxybenzoate, sodium sulfite) Etc.), thickener (eg, algin) Sodium, sodium carboxymethylcellulose, sodium polyacrylate, etc.), antioxidant (eg, dibutylhydroxytoluene, butylhydroxyanisole, ascorbic acid, tocopherol, etc.), flavor (eg, mint, strawberry flavor, etc.), acidulant (eg, Citric acid, lactose, DL-malic acid, etc.), seasonings (eg, DL-alanine, sodium 5′-inosinate, sodium L-glutamate, etc.), emulsifiers (eg, glycerin fatty acid ester, sucrose fatty acid ester, etc.), Examples include pH adjusters (for example, citric acid, trisodium citrate, etc.), vitamins, minerals, amino acids, pigments and the like. The solid composition can be produced according to a conventional method. Moreover, a liquid composition can be manufactured similarly to the liquid formulation suitable for the said oral administration.

  Moreover, food-drinks can be manufactured by mix | blending the composition of this invention, or the solid composition or liquid composition containing this composition with food-drinks. Examples of such foods and drinks include confectionery (eg, gum, candy, caramel, chocolate, cookie, snack confectionery, jelly, gummy, tablet confectionery, etc.), noodles (eg, buckwheat, udon, ramen, etc.), and dairy products. (Eg, milk, ice cream, yogurt, etc.), seasonings (eg, miso, soy sauce, etc.), soups, beverages (eg, juice, coffee, tea, tea, carbonated drinks, sports drinks, etc.) Examples thereof include foods and nutritional supplements (for example, energy drinks). The food includes foods containing food additives.

  When the composition of the present invention is used as a health food, the composition of the present invention may be used as it is, or as a form containing the composition and additives acceptable for food hygiene and normal health food ingredients. Good. The health food means a food composition for the purpose of health, health maintenance / promotion, etc., and includes an approved specific functional food and a so-called health food without the approval of the specific functional food. The health food is, for example, a liquid, semi-solid or solid product, and includes confectionery such as cookies, rice crackers, jelly, yokan, yogurt and manju, soft drinks, nutritional drinks, soups and the like. Moreover, you may melt | dissolve in hot water or water as it is, and drink. These liquid or semi-solid and solid products can be produced according to conventional methods.

  When the composition of the present invention is used as a supplement, the composition of the present invention may be used as it is, or may be a form containing the composition and an additive acceptable for food hygiene or a normal supplement raw material. . Supplements mean not only dietary supplements and functional nutritional foods to supplement nutrients, but also health supplements and functional functional foods that have functions that are useful for maintaining, restoring, and promoting health. Also means. Examples of such supplements include tablets, rounds, capsules (including hard capsules, soft capsules, and microcapsules), powders, granules, fine granules, troches, liquids (syrups, milks, suspensions). Including turbidity). These can be produced according to conventional methods.

  When the composition of the present invention is used as a feed, the composition of the present invention may be used as it is, or may be a form containing the composition and general feed additives or feed raw materials. When using the composition of this invention as a feed additive, the form which uses this composition as it is may be sufficient, and the form containing a general feed additive may be sufficient.

  When the composition of the present invention is used as a pharmaceutical product, food or drink, food additive, health food or supplement, the dose or intake of the composition is not particularly limited, for example, turmeric extract per adult per day About 13-8400 mg, preferably about 67-1700 mg of the product, if the composition contains an antioxidant, about 0.04-7500 mg, preferably about 0.20-1500 mg, for example sesamin About 0.12 to 7500 mg, preferably about 0.6 to 1500 mg, in the case of curcumin, about 0.04 to 2500 mg, preferably about 0.2 to 500 mg, in the case of ornithine, about 0.08 to 5000 mg, preferably It is preferable to administer or ingest so that the dose is about 0.4 to 1000 mg because the effect of suppressing the expression of VCAM-1 can be effectively obtained. .

Since the composition of this invention can suppress the expression of VCAM-1, it can be used as an expression inhibitor of VCAM-1. In addition, since the composition of the present invention can suppress the expression of VCAM-1, it can be used as an anti-inflammatory agent, an inhibitor of alcoholic liver injury, or an inhibitor of a decrease in the amount of behavior caused by inflammation.
That is, the present invention comprises a turmeric extract and an antioxidant substance, a VCAM-1 expression inhibitor, an anti-inflammatory agent, an alcoholic liver disorder inhibitor, and a suppression of a decrease in behavior caused by inflammation Contains agents. In these agents, the mixing ratio of the turmeric extract and the antioxidant substance and the preferred embodiment thereof are the same as those of the composition of the present invention described above.
It was unexpected that not only the combined use or blending of the turmeric extract and the antioxidant substance, but also the composition containing the turmeric extract alone as an active ingredient has an excellent VCAM-1 expression suppression effect.

In the present invention, the inflammation in the “behavior amount reduction caused by inflammation” is not particularly limited, but is preferably caused by alcohol, that is, inflammation caused by alcohol intake.
In the present invention, the behavior amount indicates the amount of human or animal behavior. The method of measuring the amount of action is not particularly limited. For example, in the case of a mouse, the amount of action may be calculated by measuring the amount of action using an infrared sensor, measuring the amount of spontaneous movement using a rotating wheel, or the like.
The measurement of the amount of action of the mouse using the infrared sensor is carried out by placing the mouse under the action quantity measuring device (Muromachi Kikai Co., Ltd., Supermex PYS-001) using the infrared sensor. It can be calculated by sensing the body temperature (far infrared rays) of the mouse with the lens and counting the number of times per hour and using the count as the amount of action.
The measurement of the spontaneous momentum of the mouse using the rotating wheel can be obtained from the number of rotations (count number) using the rotating wheel, as described in the examples described later.

In addition, since the composition of the present invention can suppress the expression of VCAM-1, a method for preventing, ameliorating or treating a disease caused by the expression of VCAM-1 (however, excluding medical practice) Can be used for. Examples of the disease caused by the expression of VCAM-1 include arteriosclerosis, rheumatism, asthma, nephritis, encephalomyelitis and the like.
That is, the composition of the present invention is characterized by preventing, ameliorating or treating a disease caused by the expression of VCAM-1.

  The present invention will be specifically described with reference to the following examples and comparative examples, but the present invention is not limited thereto.

<Turmeric extract>
Example 1
The turmeric extract was prepared by extracting the rhizome part of turmeric (Curcuma longa) with water, and drying the resulting extract under reduced pressure to remove the water. The amount of bisaclone in the turmeric extract was determined by mixing the turmeric extract solution and ethyl acetate, distilling off the ethyl acetate from the supernatant obtained by centrifugation, and using the solution dissolved in acetonitrile as the analysis sample. It calculated | required by attaching | subjecting to liquid chromatography (HPLC). HPLC was performed under the following conditions.
Column: Thermo ODS HYPERSIL (registered trademark) 250mm x φ4.6mm (manufactured by Thermo Scientific)
Mobile phase: 65% acetonitrile (20min) ⇒ 80% acetonitrile (5min) ⇒ 65% acetonitrile (10min)
Flow rate: 0.7ml / min
Temperature: 40 ° C
Detection wavelength: 242nm
As a result, the amount of bisaclone in the turmeric extract was about 0.30% by mass. Moreover, curcumin was measured by a conventional method, and it was confirmed that curcumin was not detected in the turmeric extract.

<Evaluation of VCAM-1 expression inhibitory action>
(Example 2)
Human umbilical vein vascular endothelial cells (HUVEC) were seeded in a collagen-coated 96-well plate at a concentration of 0.4 × 10 ⁵ per well, and F-12K (10% fetal calf serum, Endothelial Cell Growth Supplement 30 μg / in a 5% carbon dioxide incubator at 37 ° C. for 18 hours. Turmeric extract (140 μg / mL, 210 μg / mL, 48 μg / mL, or 160 μg / mL) or antioxidant (Sesamin (manufactured by Tokyo Chemical Industry Co., Ltd., 40 μM or 60 μM)), curcumin (manufactured by Wako Pure Chemical Industries, Ltd., 3 μM or 10 μM) Ornithine (Wako Pure Chemical Industries, 40 μM)) or a mixture thereof (a mixture of sesamin 40 μM and turmeric extract 140 μg / mL, a mixture of sesamin 60 μM and turmeric extract 210 μg / mL, a mixture of curcumin 3 μM and turmeric extract 48 μM) , F-12K (containing 2% fetal calf serum) containing 10 μM of curcumin and 160 μg / mL of turmeric extract, or 40 μM of ornithine and 140 μg / mL of turmeric extract), and 5% carbonic acid at 37 ° C. Incubated in gas incubator for 18 hours. Replace with F-12K (containing 2% fetal calf serum) containing 100 ng / mL of tumor necrosis factor-α (TNF-α) and a mixture of the above turmeric extract or antioxidant (sesamin, curcumin, ornithine) or a mixture thereof. Incubated in a 5% carbon dioxide incubator at 37 ° C. for 4.5 hours. The amount of VCAM-1 protein on the cell surface was measured by Cell-ELISA method using an anti-VCAM-1 monoclonal antibody.

FIG. 1 shows the absorbance reflecting the amount of VCAM-1 production. Moreover, the absorbance of the control and sesamin 40 μM treated products were compared by the student's t-test, and the absorbance of the treated product of the combination of turmeric extract 140 μg / mL (mixture of sesamin 40 μM and turmeric extract 140 μg / mL) was compared. Results are shown. Treatment with sesamin 40 μM was not significantly different from control, whereas treatment with turmeric extract 140 μg / mL decreased VCAM-1 production compared to control. Furthermore, the combined treatment further reduced the amount of VCAM-1 production and significantly decreased compared to the treatment with turmeric extract 140 μg / mL. This can be said to be the result of the synergistic effect that exceeds the additive action obtained by adding the actions of the two alone. In addition, as shown in FIG. 2, the treatment with sesamin 60 μM reduced the amount of VCAM-1 production by about 19% as compared to the control. Treatment with 210 μg / mL of turmeric extract reduced the amount of VCAM-1 production by about 42% as compared to the control, and significantly reduced the amount of VCAM-1 production compared to the control. Furthermore, the combination (a mixture of sesamin 60 μM and turmeric extract 210 μg / mL) decreased about 81% compared to the control, which is much higher than about 61% (19% + 42%), which is the sum of both effects. Therefore, it can be said that the synergistic effect of the two has been demonstrated.
FIG. 3 shows 3 μM curcumin and 48 μM turmeric extract, and combinations thereof, FIG. 4 shows 10 μM curcumin and 160 μg / mL turmeric extract, and combinations thereof, FIG. 5 shows ornithine 40 μM and turmeric extract, and 140 μg / mL. The results of the combined use are shown. From these results, it was confirmed that the amount of VCAM-1 produced was reduced by the turmeric extract treatment, and that a synergistic effect was exhibited by the combined use of the turmeric extract and the antioxidant.
In FIGS. S. Means no significant difference, and Ab 492 nm means that the absorbance measurement wavelength is 492 nm.

  From the above results, when the turmeric extract alone is used in the in vitro test, the concentration of the turmeric extract contained in the medium is preferably 50 μg / mL or more, and more preferably 140 μg / mL or more. .

<Evaluation of inhibitory effect on alcoholic liver injury>
(Example 3)
B6N mice with 20 mg / kg turmeric extract b. w. Orally administered so that The administration liquid used was a 0.2% (w / v) turmeric extract dispersion. Only the solvent (0.5 w / v% methylcellulose 400 solution) was orally administered to the control group of mice. After 30 minutes, 15% (w / v) ethanol solution was added at 3 g / kg b. w. Orally administered so that Blood was collected before ethanol administration and 1, 2, 4, and 6 hours after administration to prepare plasma, and AST (aspartate aminotransferase) and ALT (alanine aminotransferase) activities in plasma were transaminase CII test Wako (Wako Pure Chemical Industries, Ltd.) It measured using. FIG. 6 shows the mean ± standard deviation (Mean ± SD) of the measured values (N = 6) of AST and ALT activity at each time. Further, the measured values of the turmeric administration group and the control group at each time were compared by unmatched t-test, and the significance probability is shown in FIG. As shown in FIG. 6, turmeric extract suppresses the increase in AST and ALT induced by ethanol administration, and thus can be said to have an inhibitory action on alcoholic liver injury.

<Evaluation of the effect of alcohol administration on the decrease in locomotor activity>
Example 4
B6N mice were acclimated in a wire mesh cage for 3 days, then transferred to a plastic cage containing a rotating wheel and bred for 12 days. The breeding room was set to a 12-hour light / dark cycle (light period: 7:00 to 19:00). On the 13th day of breeding, treatment was performed according to the following schedule. On the day of treatment, water was deprived from 8:30 to 11:00 and fasted from 8:30 to 15:00. 10:30, turmeric extract 20 mg / kg b. w. Orally administered so that The administration liquid used was a 0.2% (w / v) turmeric extract dispersion. Only the solvent (0.5 w / v% methylcellulose 400 solution) was orally administered to the control group of mice. At 11:00, 3 g / kg of 15% (w / v) ethanol solution b. w. Orally (first time) so that at 15: 00, 15% (w / v) ethanol solution was 2.5 g / kg b. w. Orally administered (second time) so that On the day before and on the day of ethanol administration, the cumulative spontaneous exercise amount was measured for 3 hours (19: 00 to 22:00) from the start of the dark period. A rotating wheel (mouse rotating momentum measuring device, manufactured by Muromachi Kikai Co., Ltd., Igloo Fast Track FT-713) was installed in the breeding environment of the mouse, and the number of times the mouse turned the rotating wheel was counted to measure the spontaneous momentum. The value obtained by integrating the measured locomotor activity in units of 1 hour is taken as the integrated locomotor activity, and the ratio (%) of the integrated locomotor activity on the day of administration relative to the day before administration is calculated, and each group with and without turmeric extract (N = 7) Average values are shown in the table. In addition, the two groups were compared by an unpaired t-test, and the significance is shown in Table 1. In Table 1, P value indicates significance.

  As shown in Table 1, since the cumulative locomotor activity for 3 hours from the start of the dark period on the day of administration decreased compared to the day before ethanol administration, it can be seen that the amount of behavior of mice was reduced by ethanol administration. By comparing the case with turmeric extract and the case without turmeric extract, it was found that the decrease in accumulated spontaneous exercise amount on the day of administration relative to the day before ethanol administration was suppressed by administration of turmeric extract. That is, the turmeric extract is considered to suppress the decrease in the amount of behavior caused by inflammation caused by ethanol administration.

  Since the composition of the present invention can suppress the expression of VCAM-1, it prevents, ameliorates or treats various diseases such as inflammatory diseases caused by the expression of VCAM-1, or particularly by alcohol intake It is possible to suppress liver damage and to suppress a decrease in the amount of behavior caused by inflammation.

Claims (16)

  A composition comprising a turmeric extract and an antioxidant.   The composition according to claim 1, wherein an extraction solvent of the turmeric extract is water and / or a hydrophilic organic solvent.   The composition according to claim 1 or 2, wherein the turmeric extract contains bisaclone.   The composition according to any one of claims 1 to 3, wherein the antioxidant is one or more selected from the group consisting of sesamin or an analog thereof, curcumin, and ornithine. The composition in any one of Claims 1-4 whose compounding ratio of a bisaclone and an antioxidant substance is as follows by mass ratio.
Bisaclone: sesamin or its analogs = 1: 3 to 1: 300 or bisaclone: curcumin = 1: 1 to 1: 100 or bisaclone: ornithine = 1: 2 to 1: 200   A VCAM-1 expression-suppressing composition comprising a turmeric extract and an antioxidant.   An anti-inflammatory composition comprising a turmeric extract and an antioxidant.   A composition for suppressing alcoholic liver injury, comprising a turmeric extract and an antioxidant.   A composition for suppressing a decrease in the amount of behavior caused by inflammation, comprising a turmeric extract and an antioxidant.   The composition according to claim 9, wherein the inflammation is caused by alcohol.   The composition according to any one of claims 1 to 10, which is a prophylactic, ameliorating or therapeutic agent for diseases caused by the expression of VCAM-1.   A composition for suppressing the expression of VCAM-1, wherein the extraction solvent contains water and / or a turmeric extract that is a hydrophilic organic solvent.   An anti-inflammatory composition comprising a turmeric extract, wherein the extraction solvent is water and / or a hydrophilic organic solvent.   A composition for suppressing alcoholic liver damage, wherein the extraction solvent contains water and / or a turmeric extract which is a hydrophilic organic solvent.   A composition for suppressing a decrease in a behavior amount caused by inflammation, characterized in that the extraction solvent contains water and / or a turmeric extract that is a hydrophilic organic solvent.   The composition according to claim 15, wherein the inflammation is caused by alcohol.